Hypothalamic mechanisms mediating inhibition of prolactin secretion following stress in early pregnant mice

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Abstract

In early pregnancy prolonged exposure to stress is known to have profound adverse
effects on reproduction and is associated with suppressed progesterone secretion and
consequent disturbance of the pregnancy-protective cytokine milieu, thus threatening
early pregnancy maintenance. Maternal neuroendocrine responses to stress in early
pregnancy are poorly understood. Therefore, we designed experiments to (1) study
the hypothalamo-pituitary-adrenal (HPA) axis responses to stress in early pregnant
mice, to discover whether and how responses change and (2) to determine the effect
of stress in early gestation on pregnancy hormones, with a particular focus on the
secretion and regulation of prolactin. To establish the effects of stress in early
pregnancy (day 5.5) two different ethologically relevant stressors were used:
lipopolysaccharide (LPS) or 24h fast stress, to mimic situations that may potentially
arise during pregnancy in women: infection or hunger. HPA axis secretory responses
to immune stress in early-mid pregnancy were robust and comparable to that in
virgins. Vasopressin rather than the usual CRH neurone responses play a key role in
maintaining this. However, the mode of action of glucocorticoids in mediating
pregnancy complications is not yet established. Prolactin, and its hypothalamic
control mechanisms, is a key candidate to mediate brain-to-body responses to stress.
Prolactin has important roles in progesterone secretion, pregnancy establishment and
immune regulation. We hypothesised that stress would negatively affect prolactin
and its neuroendocrine control systems. Prolactin is mainly under the inhibitory
control of dopamine, released predominantly from the tuberoinfundibular dopamine
(TIDA) neurones. Prolactin also negatively feeds back on itself via prolactin
receptors on the TIDA neurones and janus kinase (JAK)2/signal transducer and
activator of transcription (STAT)5 signalling. Both immune and fasting stressors
strongly inhibited basal prolactin secretion in early pregnancy, accompanied by a
mild increase in activation of TIDA as shown by elevated Fos expression, compared
to virgins. In addition, pregnancy attenuated LPS-induced recruitment of parvocellular
paraventricular nucleus neurones and increased activation of brainstem
noradrenergic nuclei which could potentially contribute to altered control of the
dopamine-prolactin system. Following either immune or fast stress in early
pregnancy ovine prolactin was able to drive enhanced expression of phosphorylated
(p)STAT5. However, stress alone did not alter pSTAT5 implying it is not exclusively
responsible for the stress-reduced prolactin observed in early pregnancy and another
stress-induced stimulus must be activating TIDA neurones in these mice. LPS did not
alter dopamine activity the median eminence (DOPAC: dopamine ratio) suggesting
dopamine does not underlie stress-reduced prolactin secretion and other mechanisms
must be considered. Direct effects of LPS, or its associated cytokines, on pituitary
lactotrophs to inhibit prolactin secretion is a possible candidate. To investigate the
effect of proinflammatory cytokines on the prolactin system in early pregnancy, d5.5
mice were administered TNF-alpha (a) or interleukin (IL)-6. Both cytokines increased TIDA activation, however, only TNF-a decreased plasma prolactin and
progesterone, suggesting additional TNF-alpha action at the pituitary. As prolactin is
anxiolytic we further proposed that stress would have a more profound effect on
elevated plus maze performance in pregnant mice. However, early pregnant mice
were generally more anxious vs. virgins regardless of LPS treatment. Taken together
data show that stress in early pregnancy reduces prolactin and progesterone
secretion, contributing to pregnancy complications/failure, but the neuroendocrine
stress-related mechanism behind this suppression is yet to be determined.